Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer
Gastric cancer remains a significant global health burden, characterized by regional variations in incidence and poor survival prospects in advanced stages. Natural killer (NK) cells play a crucial role in the body’s anti-cancer defense, and chimeric antigen receptor (CAR)–NK cell therapy is gaining...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825000623 |
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| author | Yaojun Ren Min Xue Xinhui Hui Xiuyu Liu Muhammad Asad Farooq Yiran Chen Yuzhou Ji Yixin Duan Iqra Ajmal Jie Yao Wenzheng Jiang |
| author_facet | Yaojun Ren Min Xue Xinhui Hui Xiuyu Liu Muhammad Asad Farooq Yiran Chen Yuzhou Ji Yixin Duan Iqra Ajmal Jie Yao Wenzheng Jiang |
| author_sort | Yaojun Ren |
| collection | DOAJ |
| description | Gastric cancer remains a significant global health burden, characterized by regional variations in incidence and poor survival prospects in advanced stages. Natural killer (NK) cells play a crucial role in the body’s anti-cancer defense, and chimeric antigen receptor (CAR)–NK cell therapy is gaining attention as a cutting-edge and promising treatment method. This study aims to tackle the challenge of TGF-β-mediated tumor immune evasion within the immunosuppressive tumor microenvironment by designing a novel chimeric cytokine receptor TRII/21 R, which consists of extracellular domains of TGF-β receptor II (TRII) and transmembrane and intracellular domains of IL-21 receptor (21 R) and can convert the immunosuppressive signal from TGF-β in the tumor microenvironment (TME) into an NK cell activation signal through the IL-21R-STAT3 pathway. We successfully constructed NKG2D-CAR-NK cells expressing TRII/21 R and demonstrated strong anti-tumor activity against cancer cells both in vitro and in vivo. The co-expression of TRII/21 R in CAR-NK cells enhanced the cytotoxicity, promoted proliferation and survival capabilities, and reduced the expression of exhaustion markers. In the xenograft mouse model, TRII/21R-CAR-NK cells significantly inhibited tumor growth and improved the survival rate of tumor-bearing mice compared to the mice receiving control CAR-NK cells. Additionally, TRII/21 R co-expression enhanced NK cells' infiltration, activation, and persistence within the tumor, indicating a robust anti-tumor response mediated by the JAK-STAT3 signaling pathway. This study underscores the therapeutic potential of TRII/21R-modified CAR-NK cells as a breakthrough strategy for combating cancer. |
| format | Article |
| id | doaj-art-162f96f9ed964aa3b6436f88a17fbe91 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-162f96f9ed964aa3b6436f88a17fbe912025-02-08T04:59:56ZengElsevierPharmacological Research1096-11862025-02-01212107637Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancerYaojun Ren0Min Xue1Xinhui Hui2Xiuyu Liu3Muhammad Asad Farooq4Yiran Chen5Yuzhou Ji6Yixin Duan7Iqra Ajmal8Jie Yao9Wenzheng Jiang10Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China; College of Life Science, Xinjiang Normal University, Urumqi 830054, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, ChinaShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China; Correspondence to: School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.Gastric cancer remains a significant global health burden, characterized by regional variations in incidence and poor survival prospects in advanced stages. Natural killer (NK) cells play a crucial role in the body’s anti-cancer defense, and chimeric antigen receptor (CAR)–NK cell therapy is gaining attention as a cutting-edge and promising treatment method. This study aims to tackle the challenge of TGF-β-mediated tumor immune evasion within the immunosuppressive tumor microenvironment by designing a novel chimeric cytokine receptor TRII/21 R, which consists of extracellular domains of TGF-β receptor II (TRII) and transmembrane and intracellular domains of IL-21 receptor (21 R) and can convert the immunosuppressive signal from TGF-β in the tumor microenvironment (TME) into an NK cell activation signal through the IL-21R-STAT3 pathway. We successfully constructed NKG2D-CAR-NK cells expressing TRII/21 R and demonstrated strong anti-tumor activity against cancer cells both in vitro and in vivo. The co-expression of TRII/21 R in CAR-NK cells enhanced the cytotoxicity, promoted proliferation and survival capabilities, and reduced the expression of exhaustion markers. In the xenograft mouse model, TRII/21R-CAR-NK cells significantly inhibited tumor growth and improved the survival rate of tumor-bearing mice compared to the mice receiving control CAR-NK cells. Additionally, TRII/21 R co-expression enhanced NK cells' infiltration, activation, and persistence within the tumor, indicating a robust anti-tumor response mediated by the JAK-STAT3 signaling pathway. This study underscores the therapeutic potential of TRII/21R-modified CAR-NK cells as a breakthrough strategy for combating cancer.http://www.sciencedirect.com/science/article/pii/S1043661825000623Chimeric cytokine receptorCAR-NKTGF-βIL-21Gastric cancerImmunosuppressive tumor microenvironment |
| spellingShingle | Yaojun Ren Min Xue Xinhui Hui Xiuyu Liu Muhammad Asad Farooq Yiran Chen Yuzhou Ji Yixin Duan Iqra Ajmal Jie Yao Wenzheng Jiang Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer Pharmacological Research Chimeric cytokine receptor CAR-NK TGF-β IL-21 Gastric cancer Immunosuppressive tumor microenvironment |
| title | Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer |
| title_full | Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer |
| title_fullStr | Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer |
| title_full_unstemmed | Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer |
| title_short | Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer |
| title_sort | chimeric cytokine receptor tgf β rii il 21r improves car nk cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer |
| topic | Chimeric cytokine receptor CAR-NK TGF-β IL-21 Gastric cancer Immunosuppressive tumor microenvironment |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825000623 |
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